0%
PRPF8c.1855-13C>TBenign
Print report
Variant interpretation report

PRPF8 c.1855-13C>T, p.?

NM_006445.3:c.1855-13C>T NP_006436.3:p.? View identifiers
Classification
Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About PRPF8

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone

Highest observed population frequency exceeds the 1% BA1 threshold: African/African American AF 4.53% (gnomAD v2.1, 29 homozygotes) and 4.59% (v4.1, 75 homozygotes), with grpmax FAF 4.28% and 4.47% respectively; this is far too frequent for a rare autosomal dominant RP13 allele and is stand-alone benign.

BS1Strong
BS1 · strong

Overall allele frequency in gnomAD v2.1 (0.43%, 1217/281232 alleles) exceeds the 0.3% BS1 threshold, and the AFR subpopulation frequency (4.5%) far exceeds it; the variant is too frequent in reference populations to be a rare disease-causing allele.

BP4Supporting
BP4 · supporting

SpliceAI predicts no significant splice impact (max delta 0.12, below the 0.2 splice-altering threshold) for this intronic variant 13 bp upstream of exon 14, consistent with a benign effect on splicing.

Recorded classification: Benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 1 supporting benign, which maps to Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
3,888 / 1,613,640 alleles

gnomAD v4.1: 3,888 / 1,613,640 alleles. Recorded AF 0.00240946. Recorded homozygote count 77.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00432739; MAF= 0.43274%, 1217/281232 alleles, homozygotes = 30) and has highest observed frequency in the African/African American population (AF= 0.0453331; MAF= 4.53331%, 1120/24706 alleles, homozygotes = 29); grpmax FAF= 0.0427907.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0029376564030029377, 54/18382 alleles, homozygotes = 0).

Applied · BA1, BS1 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.120 maximum delta

Recorded SpliceAI maximum delta score: 0.120. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

3 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 18 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The variant is present at high population frequency in gnomAD (v2.1 overall AF 0.43%, 30 homozygotes; v4.1 AF 0.24%, 77 homozygotes), and the African/African American subpopulation AF (4.5%) and grpmax FAF (4.3-4.5%) exceed the 1% stand-alone benign threshold, far exceeding expectations for an autosomal dominant RP13 allele; BA1 is met at stand-alone benign strength.

SpliceAI predicts no significant splice impact (max delta 0.12) and ClinVar reports the variant as Benign from 3 clinical laboratories with no conflicting pathogenic assertions.

No reviewed publication reports NM_006445.3:c.1855-13C>T, so no pathogenic literature evidence applies; all ClinVar-attached PMIDs (25741868, 26666451, 20301590, 22234150, 28492532) are framework or gene-level references without variant-specific data.

Under the generic ACMG/AMP combination rules, BA1 alone is sufficient for a Benign classification, and BA1 plus BS1 (strong benign) with BP4 (supporting benign) are concordant with Benign.

Met · 3

BA1 Stand aloneHighest observed population frequency exceeds the 1% BA1 threshold: African/African American AF 4.53% (gnomAD v2.1, 29 homozygotes) and 4.59% (v4.1, 75 homozygotes), with grpmax FAF 4.28% and 4.47% respectively; this is far too frequent for a rare autosomal dominant RP13 allele and is stand-alone benign. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AFR AF 4.5333% (1120/24706 alleles
  • 29 homozygotes)
  • grpmax FAF 4.2791%
  • gnomAD v4.1 AFR AF 4.5936% (3441/74908 alleles
  • 75 homozygotes)
  • grpmax FAF 4.4656%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 StrongOverall allele frequency in gnomAD v2.1 (0.43%, 1217/281232 alleles) exceeds the 0.3% BS1 threshold, and the AFR subpopulation frequency (4.5%) far exceeds it; the variant is too frequent in reference populations to be a rare disease-causing allele. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF 0.4327% (30 homozygotes)
  • gnomAD v4.1 total AF 0.2409% (77 homozygotes) with AFR AF 4.59%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingSpliceAI predicts no significant splice impact (max delta 0.12, below the 0.2 splice-altering threshold) for this intronic variant 13 bp upstream of exon 14, consistent with a benign effect on splicing. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.12 (acceptor/donor gain/loss all below significance)
Still missing
  • SpliceAI delta 0.12 is near the 0.1-0.2 boundary
  • REVEL and BayesDel are not available for intronic variants
Sources
spliceai ↗

Not met · 18 · evaluated, threshold not reached

PS1 No pathogenic variant at the same nucleotide position (c.1855-13) has been reported; the variant is intronic with no protein consequence (p.?) so a same-amino-acid comparison is not possible. Details ▾Hide ▴
Evidence considered
  • No pathogenic comparator at c.1855-13 in ClinVar or reviewed literature
PS2 No de novo occurrence of this variant has been reported in the reviewed literature or databases. Details ▾Hide ▴
Evidence considered
  • No de novo report identified for NM_006445.3:c.1855-13C>T
Still missing
  • No de novo evidence available
PS3 No functional studies have directly tested this variant or a systematically characterized range that includes intron 13 position -13; SpliceAI predicts no splice impact (max delta 0.12). Details ▾Hide ▴
Evidence considered
  • No variant-specific functional data in any reviewed publication
  • SpliceAI max delta 0.12 indicates no significant splice effect
Still missing
  • No functional assay data for this intronic variant
Sources
spliceai ↗
PS4 No case-control or patient cohort data implicate this variant; ClinVar reports Benign from 3 clinical laboratories and population frequency is high. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV000321908: Benign
  • 3 clinical laboratories
  • No case enrichment reported in reviewed literature
Sources
clinvar ↗gnomad_v2 ↗
PM2 Population frequency (gnomAD v2.1 AF 0.43%; v4.1 AF 0.24%) far exceeds the 0.1% PM2 threshold; the variant is common in reference populations, so absence-from-controls does not apply. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF 0.4327% (1217/281232 alleles
  • 30 homozygotes)
  • gnomAD v4.1 AF 0.2409% (3888/1613640 alleles
  • 77 homozygotes)
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM6 No de novo report for this variant was identified in the reviewed literature or databases. Details ▾Hide ▴
Evidence considered
  • No de novo observation published for NM_006445.3:c.1855-13C>T
Still missing
  • No de novo evidence available
PP1 No segregation data for this variant in affected family members have been reported. Details ▾Hide ▴
Evidence considered
  • No cosegregation studies identified
Still missing
  • No segregation data available
PP2 Variant is intronic, not missense; additionally PRPF8-associated disease includes pathogenic missense variants, so a low rate of benign missense variation in the gene does not support pathogenicity here. Details ▾Hide ▴
Evidence considered
  • No missense consequence for this intronic variant
  • PRPF8 disease mechanism includes missense variants (e.g.
  • p.Tyr2334Asn) in RP mouse models
PP3 SpliceAI max delta 0.12 is below the 0.2 splice-altering threshold and predicts no significant splice impact; REVEL and BayesDel are not available for this intronic variant, so no in-silico evidence supports a damaging effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.12 (no significant splice impact)
  • REVEL/BayesDel not available for intronic variant
Still missing
  • No missense in-silico predictors applicable
Sources
spliceai ↗
PP4 No phenotype-specific data link this variant to retinitis pigmentosa or other PRPF8-associated phenotypes. Details ▾Hide ▴
Evidence considered
  • No patient phenotype data for this variant in reviewed sources
PP5 ClinVar reports the variant as Benign (not pathogenic) from 3 clinical laboratories; PP5 applies to reputable pathogenic assertions and, per the global PP5/BP6 rule, at supporting strength only for 3-star expert panel submissions, which is not the case here. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV000321908 classified Benign
  • review status 'criteria provided
  • multiple submitters
  • no conflicts' (2 stars
  • non-expert-panel)
Sources
clinvar ↗
BS2 Although homozygotes are observed in gnomAD (30 in v2.1, 77 in v4.1), the population cohort is not phenotype-confirmed healthy adults for an early-onset fully penetrant disorder; this frequency evidence is already captured under BA1/BS1. Details ▾Hide ▴
Evidence considered
  • 30 homozygotes (gnomAD v2.1)
  • 77 homozygotes (gnomAD v4.1)
Still missing
  • No clinically confirmed healthy-adult observations
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional studies demonstrating absence of a damaging effect on gene or gene product are available for this variant. Details ▾Hide ▴
Evidence considered
  • No functional assay data in reviewed literature
Still missing
  • No functional studies available
BS4 No segregation data are available showing absence of segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
  • No family segregation studies identified
Still missing
  • No segregation data available
BP2 No data are available on observation of this variant in trans with a pathogenic variant or in cis with a benign variant. Details ▾Hide ▴
Evidence considered
  • No phased/trans observations reported
Still missing
  • No allele-phase data available
BP5 No alternate molecular basis of disease (e.g., a distinct pathogenic mechanism in this gene) has been established for this case. Details ▾Hide ▴
Evidence considered
  • No alternate-molecular-basis evidence identified
BP6 ClinVar reports Benign from 3 clinical laboratories, but per the global PP5/BP6 rule BP6 is applied at supporting strength only for 3-star expert panel submissions; this record is a non-expert-panel assertion ('criteria provided, multiple submitters, no conflicts'), so BP6 is not independently applied. Details ▾Hide ▴
Evidence considered
  • ClinVar VCV000321908: Benign
  • 3 clinical laboratories (Illumina
  • ARUP
  • Labcorp)
  • Review status 2 stars
  • no expert panel
Sources
clinvar ↗
PS5 ClinVar submissions are Benign (3 clinical laboratories); no reputable source reports this variant as pathogenic, so PS5 does not apply. Details ▾Hide ▴
Evidence considered
  • All ClinVar submissions classify the variant as Benign
Sources
clinvar ↗
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AIntronic variant (NM_006445.3:c.1855-13C>T, intron 13) outside the canonical splice consensus (±1,2); the PVS1 variant assessment assigns bucket 'other' with apply_generic_pvs1_framework=false, so null-variant PVS1 does not apply. Details ▾Hide ▴
Evidence considered
  • Intronic position 13 bp upstream of exon 14
  • Not a nonsense/frameshift/canonical splice variant
  • pvs1_variant_assessment: variant_bucket='other'
  • apply_generic_pvs1_framework=false
Sources
pvs1_variant_assessmentpvs1_gene_context
PM1 N/AIntronic variant with no protein consequence; PM1 domain-level criteria for missense/in-frame changes in a critical functional domain do not apply. Details ▾Hide ▴
Evidence considered
  • No protein-level change (p.?)
PM3 N/ASkipped as trivially not applicable: PM3 requires recessive disease with the variant observed in trans with a pathogenic variant; PRPF8-associated RP13 is autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped as trivially not applicable: protein length change (in-frame indel/stop-loss) does not apply to an intronic substitution with no protein consequence. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ASkipped as trivially not applicable: intronic variant with no protein consequence; pm5_candidates.json found no same-residue missense comparator (PM5 mode 'unknown', residue context not parseable). Details ▾Hide ▴
Evidence considered
  • pm5_candidates: found=false
  • no candidates collected
Sources
pm5_candidates
BP1 N/AVariant is intronic, not a missense variant; additionally PRPF8-associated disease includes pathogenic missense variants, so BP1 (missense in a gene where only truncating variants cause disease) does not apply. Details ▾Hide ▴
Evidence considered
  • No missense consequence
  • PRPF8 missense variants are disease-associated
BP3 N/ASkipped as trivially not applicable: in-frame indel in a repetitive region does not apply to a single-nucleotide intronic substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AVariant is not a synonymous or deep intronic variant (position -13 lies near the acceptor region); splice-impact prediction is assessed under BP4. Details ▾Hide ▴
Evidence considered
  • Intronic position 13 bp upstream of exon 14
  • not deep intronic
Sources
spliceai ↗

Identifiers

Gene
PRPF8
Transcript
NM_006445.3
Coding (HGVS c.)
NM_006445.3:c.1855-13C>T
Protein (HGVS p.)
NP_006436.3:p.?
GRCh38
chr17:1677707 G>A
GRCh37
chr17:1581001 G>A
ClinVar
321908

Gene diagram

Every interpreted variant in PRPF8, mapped onto the exon structure of NM_006445.3. Select a row to find it on the plot.

PRPF8NM_006445.3
Fetching transcript structure from UCSC…
gnomAD v4.1 3,888 / 1,613,640 alleles AF 0.00241 · 77 homozygotes · FAF 0.0447
gnomAD v2.1 1,217 / 281,232 alleles AF 0.00433 · 30 homozygotes · FAF 0.0428
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.0024 · 3888 / 1,613,640 alleles · 77 hom · FAF 0.045
African/African American3441 / 74,908 0.04675 hom
Middle Eastern18 / 6,056 0.003
Remaining individuals177 / 62,496 0.00281 hom
Admixed American159 / 59,968 0.0027
South Asian20 / 91,070 0.000221 hom
European (non-Finnish)73 / 1,180,008 6.2e-05
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 0.0043 · 1217 / 281,232 alleles · 30 hom · FAF 0.043
African/African American1120 / 24,706 0.04529 hom
Admixed American71 / 35,358 0.002
Remaining individuals10 / 7,176 0.0014
South Asian8 / 30,554 0.000261 hom
European (non-Finnish)8 / 128,118 6.2e-05
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00240946; MAF= 0.24095%, 3888/1613640 alleles, homozygotes = 77) and has highest observed frequency in the African/African American population (AF= 0.0459363; MAF= 4.59363%, 3441/74908 alleles, homozygotes = 75); grpmax FAF= 0.0446555.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00432739; MAF= 0.43274%, 1217/281232 alleles, homozygotes = 30) and has highest observed frequency in the African/African American population (AF= 0.0453331; MAF= 4.53331%, 1120/24706 alleles, homozygotes = 29); grpmax FAF= 0.0427907.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0029376564030029377, 54/18382 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -104 bp
0.060
SpliceAI acceptor gainat -13 bp
0.120
SpliceAI donor lossat -381 bp
0.000
SpliceAI donor gainat -142 bp
0.040
Pangolin splice lossmagnitude shown
-0.060
Pangolin splice gain
0.210

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingSpliceAI predicts no significant splice impact (max delta 0.12, below the 0.2 splice-altering threshold) for this intronic variant 13 bp upstream of exon 14, consistent with a benign effect on splicing. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.12 (acceptor/donor gain/loss all below significance)
Still missing
  • SpliceAI delta 0.12 is near the 0.1-0.2 boundary
  • REVEL and BayesDel are not available for intronic variants
Sources
spliceai ↗
PP3 SpliceAI max delta 0.12 is below the 0.2 splice-altering threshold and predicts no significant splice impact; REVEL and BayesDel are not available for this intronic variant, so no in-silico evidence supports a damaging effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.12 (no significant splice impact)
  • REVEL/BayesDel not available for intronic variant
Still missing
  • No missense in-silico predictors applicable
Sources
spliceai ↗
BP7 N/AVariant is not a synonymous or deep intronic variant (position -13 lies near the acceptor region); splice-impact prediction is assessed under BP4. Details ▾Hide ▴
Evidence considered
  • Intronic position 13 bp upstream of exon 14
  • not deep intronic
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12).

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    Richards S et al. · 2015
    ACMG/AMP 2015 standards and guidelines for sequence variant interpretation; a framework reference that does not report any variant-specific data for PRPF8 or NM_006445.3:c.1855-13C>T.
    Does not name this variant
    PMID 25741868 ↗
  • In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa.
    Bakondi B et al. · 2016
    Reports in vivo CRISPR/Cas9 ablation of the dominant rhodopsin S334ter mutation in a rat model of autosomal dominant retinitis pigmentosa; unrelated to PRPF8 and does not mention NM_006445.3:c.1855-13C>T.
    Does not name this variant
    PMID 26666451 ↗
  • Nonsyndromic Retinitis Pigmentosa Overview.
    Adam MP et al. · 1993
    GeneReviews overview of nonsyndromic retinitis pigmentosa; a gene-level review for which neither the full text nor an abstract was available in the case materials, and no variant-specific data for NM_006445.3:c.1855-13C>T could be confirmed.
    Does not name this variant
    PMID 20301590 ↗
  • Clinical utility gene card for: BEST1-related dystrophies (Bestrophinopathies).
    Ramsden SC et al. · 2012
    Clinical utility gene card for BEST1-related dystrophies (Bestrophinopathies); discusses BEST1 testing and does not mention PRPF8 or NM_006445.3:c.1855-13C>T.
    Does not name this variant
    PMID 22234150 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Sherloc: a refinement of the ACMG-AMP variant classification criteria; a framework paper with no variant-specific data and no full text available in the case materials.
    Does not name this variant
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 3,888 / 1,613,640 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.120 Open source ↗
ClinVar 3 Benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.00240946; MAF= 0.24095%, 3888/1613640 alleles, homozygotes = 77) and has highest observed frequency in the African/African American population (AF= 0.0459363; MAF= 4.59363%, 3441/74908 alleles, homozygotes = 75); grpmax FAF= 0.0446555.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.00432739; MAF= 0.43274%, 1217/281232 alleles, homozygotes = 30) and has highest observed frequency in the African/African American population (AF= 0.0453331; MAF= 4.53331%, 1120/24706 alleles, homozygotes = 29); grpmax FAF= 0.0427907.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.0029376564030029377, 54/18382 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 321908)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).